As the outermost barrier of the body, the skin is directly exposed to a pro-oxidative environment. The effects of ultraviolet (UV) radiation from sun exposure can induce or exacerbate oxidative attack leading to the generation of reactive oxygen species (ROS) and other free radicals. The most prominent short-term effect of such skin exposure is a reddening of the skin (erythema): the most common consequence and evidence of sunburn. The most severe long-term consequence of photo-damage is skin cancer. Less severe long term photo-aging changes result in wrinkling, scaling, dryness, and uneven pigmentation consisting of hyper- and hypo-pigmentation (S R Pinneli, “Cutaneous Photodamage, Oxidative Stress, and Topical Antioxidant Protection”, J Am Acad Dermatol, 48: 1-19, 2003; J Wenk, P Brenneisen, C Meewes, M Wlaschek, T Peters, R Blaudschwun, W. Ma, L. Kuhr, L Schneider, and K. Scharftetter-Kochanek, UV-Induced Oxidative Stress and Photoaging, in J Thiele and P. Elsner, Ede. Oxidants and Antioxidants in Cutaneous Biology, Current Prob. Dermatol. Basel, Karger, 29: 2001, pp 83-94; M Berneburg, H Plettenberg, and J Krutmann, Photoaging of Human Skin, Photodermatol Photoimmunol Photomed, 16: 239-244, 2000).
Extended life-span, more spare time and excessive exposure to UV radiation from sunlight or tanning devices, especially in the western population, has resulted in an ever increasing demand to protect human skin against the detrimental effects of UV-exposure. Sunscreens—the current gold standard of photo-protection—are useful, but their protection is most often inadequate due to improper and/or non-optimal application. Furthermore, most sunscreens are not suitably effective against long wave UV-A light due to the poor selectivity of most sunblock actives for UV-A and because UV-A is especially efficient at generating reactive oxygen species (ROS) (M Wlaschek, K Briviba, G P Stricklin, H Sies, K Scharfetter-Kochanek, J Invest Dermatol, 104: 194-198, 1995; M Berneburg, S Grether-Beck, V Kurten, T Ruzicka, K Briviba, H Sies and J Krutmann, Singlet Oxygen Mediates the UV-induced Generation of the Photoaging-Associated Mitochondrial Common Deletion, J Biol Chem, 274: 15345-15349, 1999; R Haywood, P Wardman, R Sanders and C Linge, Sunscreens Inadequately Protect Against Ultraviolet-A-Induced Free Radicals in Skin: Implications for Skin Aging and Melanoma, J Invest Dermatol, 121: 862-868, 2003). Although the principal focus of sunscreen products has traditionally been on UV-B due to its highly damaging nature, UV-A is being recognized increasingly as an important cause of photo-aging and skin cancer.
Furthermore, because, photo-aging of skin is a complex biological process affecting various layers of the skin with major changes seen in the connective tissue of the dermis, the natural shift toward a more pro-oxidant state in intrinsically aged skin can be significantly enhanced following UV-irradiation. Through the evaluation of punch biopsies of human skin following UV irradiation, Brennan et. al. have identified MMP-1 as the major collagenolytic enzyme responsible for collagen damage in photoaging (M Brennan, H Bhatti, K C Nerusu, N Bhagavathula, S Kang, G J Fisher, J Varani and J J Voorhees, Matrix Metalloproteinase-1 Is The Major Collagenolytic Enzyme Responsible for Collagen Damage in UV-Irradiated Human Skin, Photochem Pholobiol, 78: 43-48, 2003). In contrast, the synthesis of tissue inhibitory metalloprotease-1 (TIMP-1), the natural inhibitor of matrix metalloprotease, increases only marginally. This imbalance is one of the causes of severe connective tissue damage resulting in photo aging of the skin. Although collagen content decreases, collagen synthesis in sun-damaged skin appears to remain similar to that of sun-protected sites (A Oikarinen, M. Kallionen, Biochemical and Immunohistochemical Study of Collagen in Sun-Exposed and Protected Skin, Photodermatology, 6: 24-31, 1989; E Schwartz, F A Crickshank, C C Christensen, J S Perlish, and M Lebwohl, Collagen Alterations in Chronically Sun-Damaged Human Skin, Photochem Photohiol, 58: 841-844, 1993). Thus, evidence suggests that the decrease in collagen content in photo-damaged skin results from increased collagen degradation, by matrix metalloprotease, without significant changes in collagen production (E F Bernstein and J Uitto, The Effect of Photodamage on Dermal Extracellular Matrix, Clinics in Dermatology, 14: 143-151, 1996).
The damage caused by excessive MMP on the ECM proteins does not appear overnight, but results from the accumulation of successive instances of molecular damage, especially in the case of overexposure to UV light. The skin repercussion on the degradation of the ECM proteins may then be revealed in many ways depending on age, genetic predisposition, and life-style and, of course, on the general health status of the individual (A Oikarinen, The Aging of Skin: Chronoaging Versus Photoaging, Photderm, Photoimmun. Photomed., 43: 3-4, 1990).
Whether extrinsic or intrinsic, these factors result in visible signs of skin aging and environmental damage, such as wrinkling and other forms of roughness (including increased pore size, flaking and skin lines), and other histological changes associated with skin aging or damage. The elimination of wrinkles has become a booming business in youth-conscious societies. Extrinsic or intrinsic factors may result in the thinning and general degradation of the skin. For example, as the skin naturally ages, there is a reduction in the cells and blood vessels that supply the skin. There is also a flattening of the dermal-epidermal junction which results in weaker mechanical resistance of this junction. See for example, Oikarinen, “The Aging of Skin: Chronoaging Versus Photoaging,” Photodermatol. Photoimmunol. Photomed., vol. 7, pp. 3-4, 1990, which is incorporated by reference herein in its entirety.
Many sunscreen preparations are sold commercially or are described in cosmetic or pharmaceutical literature. Ideally, sunscreen compositions should be nontoxic and non-irritating to the skin tissue and be capable of convenient application in a uniform continuous film. The product should be chemically and physically stable so as to provide an acceptable shelf life upon storage; and, it is particularly desirable that the preparation should retain its protective effect over a prolonged period after application. In general, sunscreen preparations are formulated as creams, lotions, oils or sprays containing, as the active agent, an inorganic additive that physically blocks the UV rays or an organic compound that absorbs ultra violet radiation, or combinations thereof. The sunscreen preparation works by blocking, physically or chemically, passage of ultra violet radiation thereby preventing its penetration into the skin.
According to Zecchino et al, (U.S. Pat. No. 5,008,100), sunblock active agents may be characterized in the order of decreasing effectiveness as either highly chromophoric (monomeric organic compounds and inorganic compounds such as titanium dioxide) and minimally chromophoric (polymeric organic solids).
Organic sunscreens are classified into UV-A filters, UVB filters or broad spectrum filters (UV-A and UVB functionality in a single molecule) depending on the type of radiation they absorb. UV-A sunscreens absorb radiation in the 320 to 400 nm regions of the ultra violet spectrum and UV-B sunscreens absorb radiation in the 290 to 320 nm regions of the ultra violet spectrum (See Sunscreens, Regulations and Commercial Development, Third Edition, Ed Nadim A. Shaath, Taylor & Francis, 2005), Broad-band sunscreens (UV-A and UVB functionality) absorb radiation in the 290 to 400 nm region of the ultra violet spectrum and have two maximums, one in the UV-B region and the other in the UV-A region, Representative references relating to UV sunscreens include Gonzalez et. al.—U.S. Pat. No. 7,186,404; Aust et. al.—U.S. Pat. No. 7,175,834; Roseaver et. al.—U.S. Pat. No. 7,172,754; Simoulidis et. al.—U.S. Pat. No. 7,175,835; Mongiat et. al.—U.S. Pat. No. 7,101,536; Maniscalco—U.S. Pat. No. 7,078,022; Chaudhuri et. al.—U.S. Pat. No. 6,165,450; Forestier et. al. U.S. Pat. No. 5,175,340; and Wang et. al. U.S. Pat. No. 5,830,441.
Unfortunately, some of the highly chromophoric monomeric organic compounds employed in sunscreen compositions are not photostable and the protection from sun damage is lost after only a short period of time. For example, Avobenzone, a UV-A sunscreen, is generally photo-unstable. Furthermore, photo-instability of Avobenzone increases significantly when combined with Octyl methoxycinnamate (a UV-B organic sunscreen). In most studies, Octyl methoxycinnamte (OMC) has been regarded as relatively photostable. The absorption maxima of Avobenzone (about 360 nm) and OMC (about 310 nm) do not overlap sufficiently to allow directly excited singlet-singlet energy transfer to occur. However, transfer from one excited triplet-state to another is possible provided the energy levels are suitable. Techniques for stabilizing UV absorbent compositions are known. Representative disclosures in this area include Forestier et. al.—U.S. Pat. No. 5,567,418, U.S. Pat. No. 5,538,716, and U.S. Pat. No. 5,951,968; Deflandre et. al.—U.S. Pat. No. 5,670,140; Chaudhuri—U.S. Pat. No. 7,150,876, U.S. Pat. No. 6,831,191, U.S. Pat. No. 6,602,515, U.S. Pat. No. 7,166,273, U.S. Pat. No. 6,936,735, U.S. Pat. No. 6,831,191, and U.S. Pat. No. 6,699,463; Chaudhuri et al.—U.S. Pat. No. 7,150,876; and Bonda et. al. U.S. Pat. No. 6,962,692.
In an effort to address some of the shortcomings of typical sunscreen compositions, certain manufacturers have added antioxidants. Antioxidants are believed to provide protection from free-radical damage by quenching or sequestering free radicals generated by UV exposure. Photo-protective products combining sunscreens and an antioxidant or antioxidant mixtures have been touted as providing increased efficacy and safety relative to UV exposure (S R Pitmen, Cutaneous Photodamage, Oxidative Stress, and Topical Antioxidant Protection, J Am Acad Dermatol, 48: 1-19, 2003). To be an effective quencher, it is believed that the antioxidant must be present in an adequate concentration at the site of free radical generation. However, since antioxidants are used in relatively low concentrations and are a separate ingredient, they may not be available at the site of free radical generation. Consequently, the level of skin protection may be reduced and, oftentimes, less than desired.
While the general use of antioxidants in sunscreen formulations is advocated, it is often disregarded that these compounds not only function as antioxidants, but intrinsically have pro-oxidant action as well, especially in the presence of transition metals (See e.g., “Role of Antioxidants in Sun Care Products” by R. Chaudhuri in Sunscreens, N A Shaath, editor, Taylor and Francis, p 603-638, 2005). There is pro-oxidant action even in well-known antioxidants, such as, vitamin C (ascorbate), vitamin E (tocopherols), glutathione and proanthocyanidins (from pine and grape). The pro-oxidant activity of vitamin C results from the reduction of Fe3+ to Fe2+ and its reaction with H2O2 to generate OH radicals. Pro-oxidant effects are not unique to vitamin C: they can be demonstrated with many reducing agents, including vitamin E, glutathione and several plant phenolic compounds, in the presence of transition metal ions. Thus, if vitamin C's pro-oxidant effects are relevant, the pro-oxidation effects of these other reductants may also be expected to occur.
While the objective of sunscreens is, in general, to prevent skin damage due to UV exposure, such also prevents, in many instances, the skin darkening effect, or tanning, desired by many sunbathers. So as not to completely disappoint those desirous of a bronze look, formulators oftentimes add self-tanning agents such as dihydroxyacetone (DHA) to their sunscreen compositions. DHA is an intermediate of carbohydrate metabolism in higher plants and animals: commonly present as the dihydroxyacetone monophosphate in glycolysis. In crystalline form, DHA is a mixture of one monomer and four dimers: though an all monomer form may be generated by heating or melting dimer DHA or by dissolving it in water.
The reaction product of DHA and the skin protein that produces the “tan” color has been shown to provide protection against UV-A in animals and humans (Self-Tanners: Formulating with Dihydroxyacetone, R. Chaudhuri & C Hwang, Cosmetics & Toiletries, 116:87-96, 2001; Dihydroxyacetone: Chemistry and Applications in Self-Tanning Products, R. Chaudhuri, in The Chemistry and Manufacture of Cosmetics, Ed, M Schlossman, Allured publishing, 3rd Edition, 383-402, 2002). Experimental and clinical evidence show that skin that has been treated topically with 3% DHA solution overnight has a Sun Protection Factor (SPF) of at least 3 in the UV-B region. Likewise, a photoprotection factor of 10 in the UV-A region has been observed with 15% solution of DHA. Unfortunately, DHA is photochemically very unstable and it takes a long time to get a very little skin protection against sun-induced skin damage (Self-Tanners: Formulating with Dihydroxyacetone, R. Chaudhuri & C Hwang, Cosmetics & Toiletries, 116:87-96, 2001).
Despite all the efforts that have been undertaken to formulate effective sunscreen compositions and despite the constant reminders of the importance of proper and adequate application, current sunscreen products are not entirely effective. Either the formulation is not fully effective, or at least not at the time of application, or its application is faulty or improper: most often a little of both. Presently available sunscreen compositions are, for the most part, ineffective against Reactive Oxygen Species induced and/or enzyme induced skin damage. Additionally, the products are oftentimes chemically and physically unstable, having poor or moderate shelf life upon storage and/or fail to retain its protective effect over a prolonged period after application. Furthermore, it is merely a matter of reality that those who apply the sunscreen often do so improperly or ineffectively: particularly when it comes to the timely re-application of the sunscreen product and/or its re-application following certain activities, such as swimming, washing face and hands, etc. Consequently, the user oftentimes finds him or herself with a sunburn, and the concomitant underlying damage manifested by the sunburn inducing UV exposure, despite their best efforts.
Thus, there is a continuing need and effort to formulate sunscreen compositions that are more effective and more forgiving and have improved physical and chemical stability.
Furthermore, since sunscreens are not utopian and there is and always will be the human factor relative to their application, it would also be especially desirable to provide a sunscreen product that not only protects one's skin from the damaging effects of UV exposure, but also improves the health and/or physical appearance of the skin and/or repairs past skin damage, whether due to UV exposure or merely as a result of natural aging.
Surprisingly, it has now been found that effective sunscreen compositions having many, if not most, of the desired attributes of the utopian, or nearly utopian, sunscreen composition may be prepared by the further incorporation therein of an effective amount of one or more purified meroterpenes or meroterpene enriched extracts.
Furthermore, it has now been found that the combination of traditional sunblock actives and meroterpenes or enriched meroterpene extracts in a sunscreen composition provide a performance synergy in preventing damage due to UV exposure as well as in mitigating the manifestation of said damage, particularly in the short term time frame. These compositions also have improved stability and utility in many cosmetic applications, enabling sunscreen application concurrent with one's application of their cosmetics